Pharmacological differentiation of dopamine D-1 and D-2 antagonists after single and repeated administration.

Abstract

In single-dose experiments neuroleptics antagonize dopamine (DA)-agonist-induced stereotypies in animals. The antagonistic potency correlates with their clinical antipsychotic effects. In a series of experiments where DA-agonist-induced stereotyped gnawing in mice and rats was inhibited by neuroleptics it was shown that the antagonistic effect of butyrophenones was greatly attenuated by concomitant treatment with anticholinergics. The effect of phenothiazines was slightly attenuated and that of thioxanthenes and SCH 23390 remained unchanged. After repeated administration a differentiation is also seen in the ability of the antagonists to suppress DA-agonist-induced stereotypies. The differentiation in these experiments is similar to that seen in dopamine D-1 and D-2 receptor binding. The compounds can be classified into three pharmacological subgroups: butyrophenones (e.g., haloperidol) with affinity for D-2 receptors; phenothiazines (e.g., fluphenazine and perphenazine) with affinity for both D-2 and D-1 receptors but with preference for the D-2 receptors; and thioxanthenes (e.g., cis(Z)-flupentixol and cis(Z)-clopenthixol) with equal affinity for D-1 and D-2 receptors, and the selective D-1 antagonist SCH 23390. This compound has the same antistereotypic effect as is seen with the neuroleptics. We have also investigated the effect of the above-mentioned neuroleptics and SCH 23390 after 12 days' treatment and 3-5 days withdrawal. They were given either alone or in combination. When they were given alone a clear differentiation was seen between the groups when mice were tested for methylphenidate antagonism. The thioxanthenes and SCH 23390 retain their ability to antagonize the stereotyped gnawing; the phenothiazines show a reduced effect; and the butyrophenones have almost lost their ability to antagonize the stereotyped behavior.